TY - JOUR
T1 - E2112
T2 - Randomized Phase III Trial of Endocrine Therapy Plus Entinostat or Placebo in Hormone Receptor–Positive Advanced Breast Cancer. A Trial of the ECOG-ACRIN Cancer Research Group
AU - Connolly, Roisin M.
AU - Zhao, Fengmin
AU - Miller, Kathy D.
AU - Lee, Min Jung
AU - Piekarz, Richard L.
AU - Smith, Karen L.
AU - Brown-Glaberman, Ursa A.
AU - Winn, Jennifer S.
AU - Faller, Bryan A.
AU - Onitilo, Adedayo A.
AU - Burkard, Mark E.
AU - Budd, George T.
AU - Levine, Ellis G.
AU - Royce, Melanie E.
AU - Kaufman, Peter A.
AU - Thomas, Alexandra
AU - Trepel, Jane B.
AU - Wolff, Antonio C.
AU - Sparano, Joseph A.
N1 - Funding Information:
This study was coordinated by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD, and Mitchell D. Schnall, MD, PhD, Group Cochairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: CA180820, CA180794, CA180802, CA180795, CA180799, CA189956, CA189830, CA189856, CA180888, CA180866, CA180821, CA180868, CA180822, CA189859, CA180853.
Publisher Copyright:
Copyright © 2022 American Society of Clinical Oncology. All rights reserved.
PY - 2021/10/1
Y1 - 2021/10/1
N2 - PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio 5 0.87; 95% CI, 0.67 to 1.13; P 5 .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio 5 0.99; 95% CI, 0.82 to 1.21; P 5 .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
AB - PURPOSE Endocrine therapy resistance in advanced breast cancer remains a significant clinical problem that may be overcome with the use of histone deacetylase inhibitors such as entinostat. The ENCORE301 phase II study reported improvement in progression-free survival (PFS) and overall survival (OS) with the addition of entinostat to the steroidal aromatase inhibitor (AI) exemestane in advanced hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancer. PATIENTS AND METHODS E2112 is a multicenter, randomized, double-blind, placebo-controlled phase III study that enrolled men or women with advanced HR-positive, HER2-negative breast cancer whose disease progressed after nonsteroidal AI. Participants were randomly assigned to exemestane 25 mg by mouth once daily and entinostat (EE) or placebo (EP) 5 mg by mouth once weekly. Primary end points were PFS by central review and OS. Secondary end points included safety, objective response rate, and lysine acetylation change in peripheral blood mononuclear cells between baseline and cycle 1 day 15. RESULTS Six hundred eight patients were randomly assigned during March 2014-October 2018. Median age was 63 years (range 29-91), 60% had visceral disease, and 84% had progressed after nonsteroidal AI in metastatic setting. Previous treatments included chemotherapy (60%), fulvestrant (30%), and cyclin-dependent kinase inhibitor (35%). Most common grade 3 and 4 adverse events in the EE arm included neutropenia (20%), hypophosphatemia (14%), anemia (8%), leukopenia (6%), fatigue (4%), diarrhea (4%), and thrombocytopenia (3%). Median PFS was 3.3 months (EE) versus 3.1 months (EP; hazard ratio 5 0.87; 95% CI, 0.67 to 1.13; P 5 .30). Median OS was 23.4 months (EE) versus 21.7 months (EP; hazard ratio 5 0.99; 95% CI, 0.82 to 1.21; P 5 .94). Objective response rate was 5.8% (EE) and 5.6% (EP). Pharmacodynamic analysis confirmed target inhibition in entinostat-treated patients. CONCLUSION The combination of exemestane and entinostat did not improve survival in AI-resistant advanced HR-positive, HER2-negative breast cancer.
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U2 - 10.1200/JCO.21.00944
DO - 10.1200/JCO.21.00944
M3 - Article
C2 - 34357781
AN - SCOPUS:85116795237
SN - 0732-183X
VL - 39
SP - 3171
EP - 3181
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 28
ER -